The present invention concerns methods of reducing aluminum levels, amounts or concentrations in the central nervous system in patients or subjects in need thereof, such as Alzheimer""s disease patients or patients at risk of developing Alzheimer""s disease.
Alzheimer""s disease is a devastating neurological disease that is characterized by progressive and increasing memory loss, followed by loss of control of limbs and bodily functions and eventual death. As the life expectancy in the United States and elsewhere has progressed, the number of individuals afflicted with Alzheimer""s disease has grown accordingly. Currently, approximately 4 million Americans (one in five of those 75 to 84 years of age and nearly half of those 85 years old and older) are now afflicted. See Newsweek, pg 48 (Jan. 31, 2000).
A variety of treatments are in development for Alzheimer""s disease, and a few have been introduced. For example, U.S. Pat. No. 5,935,781 to Poirier describes the treatment of Alzheimer""s disease with cholinomimetic drugs, and U.S. Pat. No. 5,523,295 to Fasman describes the treatment of Alzheimer""s disease by administering a silicon compound capable of interaction between aluminum and xcex2-amyloid or neurofilament proteins. Nevertheless, there remains a need for new ways to treat Alzheimer""s disease.
The Ts65Dn (Ts) mouse contains a trisomic segment of murine chromosome 16 (MMU 16) that extends from an anonymous DNA locus, just proximal to the beta amyloid precursor protein (xcex2-APP), to the end of the long arm (Davisson et al., In: The Phenotypic Mapping of Down Syndrome and Other Aneuploid Conditions. (ed. C. J. Epstein), pp.117-133. New York, N.Y.: Wiley-Liss, Inc. (1993); Kola and Hertzog, Genetics and Development 8, 316-321 (1998)). Portions of the genes encoded on this segment are homologous to those within the xe2x80x9cDown syndrome critical regionxe2x80x9d, cytogenetically classified as band 21q22 of human chromosome 21 (Davisson et al., supra). Several studies have reported similarities between Ts mice and Down syndrome (DS) individuals (Davisson et al.,supra; Escorihuela et al., Neurosci. Lett., 199, 143-146 (1995); Reeves et al., 1995; Holtzman et al., Proc. Natl. Acad. Sci USA, 93, 13333-13338 (1996); Cefalu et al. Growth Dev. and Aging, 62, 47-59 (1998); Kola and Hertzog, supra).
Cefalu et al. (supra) reported the Ts mouse exhibited decreased efficiency of intestinal absorption, shorter and thinner intestinal villi, lower whole-body oxygen consumption, elevated plasma concentrations of phenyl-alanine, tyrosine, citrulline, ornithine and decreased concentrations of hydroxyproline. The branched chain amino acids (BCAA); leucine, isoleucine, and valine were significantly elevated in Ts mice when compared to controls. In addition, Cefalu et al. confirmed previous reports of hyperactivity (Davisson et al.,supra), and small body size (Holtzman et al.,supra) of Ts mice compared to their control littermates.
PYY is composed of 36 amino acids and is a member of the pancreatic polypeptide family (Taylor, Growth Dev. and Aging, 62, 47-59 (1989)). It has been proposed as the putative humoral agent in the xe2x80x9cileal brakexe2x80x9d phenomenon (Taylor, supra; Pironi et al., Gastroenterology, 105, 733-739 (1993); Lin et al., Gastroenterology, 110, 1491-1495 (1996)), although recent publications have disputed this hypothesis (Raybould et al., Regulatory Peptides, 79, 125-130 (1999); Zhao et al., Regulatory Peptides, 79, 125-130. (1999)). Bird et al. J. Anim. Sci., 74, 2523-2540 (1996) first described the ability of exogenous PYY to enhance intestinal glucose uptake and the apparent energetic efficiency of glucose uptake (APEE) in mice. Infusion of PYY to conscious dogs has enhanced small intestinal water and electrolyte absorption in the fasting state (Bilchik et al., Gastroenterology, 105, 1441-1448 (1993)) and nutrient absorption in the post prandial state (Bilchik et al., Am. J. Surgery, 167, 6, 570-574 (1994)).
There is a high incidence of Alzheimer""s disease (AD) in DS persons over the age of 40 (Schupf et al., Neurology, 50, 991-995 (1998)). Some studies indicate the Ts mouse brain displays AD neuropathology (Holtzman et al., supra), while others do not (Reeves et al., Nature Genetics, 11, 177-184 (1995)). Elevated brain aluminum (Al) content is a putative risk factor for AD (Savory et al., Journal of Toxicology and Environmental Health, 48, 615-635 (1996)). Aluminum is thought to enter the body primarily through intestinal absorption (Rogers and Simon, Age and Aging, 28, 205-209 (1999)). A recent study has shown Down syndrome persons absorb more Al from their intestinal tract than diploid controls (Moore et al., Biological Psychiatry, 41, 488-492 (1997)). Aluminum levels have not been studied in Ts mice.
A first aspect of the present invention is a method of reducing aluminum concentrations, levels, or amounts in the central nervous system of a subject in need thereof. The method comprises administering to said subject a PYY receptor agonist in an amount effective to reduce aluminum concentrations, levels or amounts in the central nervous system of the subject.
A particular aspect of the present invention is a method of treating Alzheimer""s disease in a subject in need thereof, comprising administering to the subject a PYY receptor agonist in a treatment effective amount (e.g., an amount effective to reduce aluminum levels in the brain of the subject, or reduce or slow aluminum uptake in the brain of the subject).
Administering steps herein may be carried out chronically or acutely (or situationally) by any suitable route, including but not limited to parenteral and oral administration, nasal and inhalation administration, etc.
PYY receptor agonists, this term including the pharmaceutically acceptable salts thereof, are sometimes referred to as xe2x80x9cactive compoundsxe2x80x9d or xe2x80x9cactive agentsxe2x80x9d herein. A still further aspect of the present invention is the use of such active agents for the preparation of a medicament for the treatment of Alzheimer""s disease or inhibiting or reducing brain aluminum levels in a subject in need thereof.
A still further aspect of the present invention is a composition comprising, in combination, a first active agent for treating Alzheimer""s disease and a second (i.e. different) active agent for treating Alzheimer""s disease, wherein said first active agent is a PYY receptor agonist. The composition may further comprise a pharmaceutically acceptable carrier. The second active agent may be any suitable active agent, including but not limited to cholinomimetic drugs, nonsteroidal anti-inflammatory agents, histamine H2 receptor blocking agents, silicon compounds capable of interaction between aluminum and xcex2-amyloid or neurofilament protein, and proteinase inhibitors. The second active agent may be a centrally active anticholinesterase such as tacrine. The composition may be provided in any suitable form, such as an oral dosage composition.
The present invention is explained in greater detail in the specification set forth below.